Cyclopentanophenanthrene derivatives and method for the production thereof



United States Patent CYCLOPENTANOPHENANTHRENE DERIVA-- TIVES AND METHOD FOR THE PRODUC- TION THEREOF Claims priority, application Mexico June 5, 1954: '7 Claims. (Cl. 260-3973) The present invention relates to novel cyclopent anophenanthrene derivatives and to a process for the pro- 1 duction thereof.

More particularly, the present invention relates to a novel process for the production of the known androgenic hormone, A -androsten-17a-ol-3-one, the 'l7-sterefoisomer. of testosterone. This compound whichis also known as isotestosterone and epitestosterone is ordinarily formed in very small amounts as a secondary product in some of the commercial processes for the manufacturer 1 of testosterone, Where it occurs together with the predominant [3 isomer. A -androsten-l7ot-ol 3-one.is known to be an active androgenic hormone, although itsactivity with regard to androgenic effects is somewhat less than that of testosterone. The compound, however," has valuable anabolic and/or other properties'which character- COOH- decarboxylation 2,842,565 Patented July 8, 1958 l oxidation manganese dioxide In practicing the process above outlined in the first step, Bfl-hydroxy-A -etiocholadienic acid is decarboxylated as by refluxing with quinoline preferably in the presence of copper chromite. For this step of the reaction the 3B-hydroxy-A -etiocholadienic acid is dissolved in the quinoline and mixed with a small quantity of copper chromite. The mixture is then refluxed for a substantial period of time, i. e. of the order of 'four hours, cooled and poured into water. The product is then extracted with an organic solvent such as ether and purified to produce A i-androstadien-Zifi-ol.

"*For' the second step of the process above-outlined the A -androstadien-3,8-01 is subjected to Oppenhauer oxidation. This involves. the use of an inert solvent, such as toluene, a hydrogen acceptor, preferably a ketone hydrogen acceptor such as cyclohexanone and an aluminum alkoxide, as for example aluminum isopropylate. The starting compound is dissolved in the toluene and cyclohexanone and the mixture is preferably distilled for Aluminum alkoxide, hydrogen acceptor aromatic Deracid O 7 reduction lithium aluminum hydride a short period of time in order to remove traces of moisture. Thereafter, the aluminum isopropylate dissolved in toluene is added and the mixture refluxed for a period of time of the order of one hour. The reaction mixture isthen poured into water and purified as by steam distillation. After further purification, there was obtained A -andrOStadien-B-one, a known compound characterized a strong, urine-like smell.

The A -androstadien-3-one is then subjected to se- 'lective formation of the corresponding 16,17-epoxide. A suitable oxidizing agent for this purpose is an aromatic peracid, as for example perbenzoic acid, or monoperphthalic acid. For the oxidation the n androstadien- 3-one is dissolved in a suitable organic solvent such as chloroform and mixed with a solution, as for example an ether solution of perbenz'oic acid. The mixture is then kept standing at a temperature of about room temperature for approximately one day. After suitable purification, the 16,17-epoxide of A -androsten-3-one is obtained.

The epoxide obtained in accordance with the previous step just referred to. is then reduced with lithium alu- Example I 1 g. of crude 3fl-hydroxy-A -etiocholadienic acid was dissolved in cc. of distilled quinoline and mixed with 100 mg. of copper chromite. The mixture was refluxed for four hours, cooled, poured into water and the product p tone-hexane and had a melting point of 140141 C., 1

[0:1 66 (chloroform).

Example II 10 g. of A -androstadien-3/3-ol was dissolved in 475 cc. of toluene and 75 cc. of cyclohexanone and 50 cc. of the mixture was distilled in order to remove traces of moisture. 5 g. of aluminum isopropylate dissolved in 50 cc. of anhydrous toluene was then added and the mixture was refluxed for one hour under anhydrous conditions. steam distilled and cooled and the precipitate formed was filtered, dried on the funnel and dissolved in chloroform. Some insoluble matter was removed by filtration and the solution was evaporated nearly to dryness and crystallized by the addition of hexane. Therewas obtained 8 g. of A -androstadien-3- one with a melting point of 130133 C., a substance which is characterized by its strong urine-like smell. The analytical sample, prepared by two further recrystallizations from chloroform-hexane, had a melting point of 132134 C. 0n direct comparison, this substance proved to be identical to a sample prepared in accordance with the method described by Prelog, Ruzicka, Meister and Wieland Helv. Chim. Acta 28, 618, 1945.

Example III 3 g. of A -androstadien-3-one was dissolved in 5 cc. of chloroform and mixed with 33.5 cc. of an ether solution of perbenzoic acid containing 0.042 g. of peracid per cc. and the mixture was kept standing atroom temperature for sixteen hours. added and the solution was washed with dilute sodium carbonate solution and water until neutral, dried over sodium sulfate and evaporated to dryness. The odorless residue was chromatographed in a column with 150 g. of washed alumina. the column with hexane-benzene (20-80) and with benzene were recrystallized from chloroform-hexane, thus yielding 2.1 g. of crystals of the 16.17-epoxide of A ance with Example III in 130 cc. of anhydrous tetrahydrofurane was added to a suspension of 3 g. of lithium After pouring into water, the mixture was More chloroform was The fractions eluted from androsten-3-one with a melting point 082088-2111 C. a

aluminum hydride in 30 cc. of anhydrous tetrahydrofuran The mixture was refluxed for two hours under 4 anhydrous conditions, cooled and the excess of hydride was destroyed by the cautious addition of water. Chloroform was added, followed by saturated sodium sulfate solution and some anhydrous sodium sulfate and the precipitate of inorganic salts was filtered and washed with chloroform. The organic solution was evaporated to dryness and the precipitate (mixture of isomeric A androstenediols) was dissolved in 300 cc. of chloroform, mixed with 15 g. of manganese dioxide and the mixture was shaken for 14 hours. 6 additional grams of manganese dioxide was added and the stirring was continued for a further 22 hours. The solution was filtered, evaporated to dryness and the residue was chromatographed in a column of aluminum oxide, thus giving 1.76 g. of isotestosterone with a melting point of 213 216 C. The substance had an [a] -}-69- (ethanol), +86 (chloroform), and an ultraviolet absorption maximum )t max. 240 m (log 64.2)- The melting point in mixture with an authentic sample of isotestosterone suffered no depression. A'mixture of mg. of isotestosterone, 2 cc. of anhydrous pyridine and 2 cc. of acetic anhydride was heated on the steam bath for one hour and poured into water. The precipitate was collected, washed to neutral and crystallized from acetone hexane, thus giving 100 mg. of the acetate of isotestosterone, with a melting point of ,113-115 C.

We claim: 1. A process for the production of A -androsten-17aol-3-one which comprises decarboxylating 3fi-hydroxy- A -etiocholadienic acid to form A -androstadien-3B- lol, treating A -androstadien-3;8-ol with an aluminum alkoxide in the presence of a hydrogen acceptor to form 'A -androstadien-3-one, oxidizing the last mentioned compound with an aromatic peracid to form the corres'pouding 16,17-epoxide, reducing the 3-keto group and the epoxide with lithium aluminum hydride to form a :mixture of A -androsten-3a,17a-dio1 and M-androsten- 35,17u-diol and selectively oxidizingthe 3-hydroxy group of the mixture with manganese dioxide.

2. A process for the production of A -androstadien- 3 3-01 which comprises refluxing 3p-hydroxy-A -etiocholadienic acid with quinoline.

3. A process for the production of A -androstadien- 3fl ol which comprises refluxing 3,8-hydroxy- -etiocholadienic acid with quinoline. in the presence of copper References Cited in the file of this patent UNITED STATES PATENTS 2,109,400 Miescher Feb. 23, 1938 2,212,014 Schwenk Aug. 20, 1940 2,374,370 Miescher Apr. 24, 1945 2,430,988 Marker Nov. 18, 1947 2,673,847 Spero May 30, 1954 2,686,181 Julian Aug. 10, 1954 

1. A PROCESS FOR THE PRODUCTION OF $4-ANDROSTEN-17AOL-3-ONE WHICH COMPRISES DECARBOXYLATING 3B-HYDROXY$5-16-ETIOCHOLADIENIC ACID TO FORM $5-16-ANDROSTADIEN-3BOL, TREATING $5,16-ANDROSTADIEN-3B-36 WITH AN ALUMINUM ALKOXIDE IN THE PRESENCE OF A HYDROGEN ACCEPTOR TO FORM $4,16-ANDROSTADIEN-3-ONE, OXIDIZING THE LAST MENTIONED COMPOUND WITH AN AROMATIC PERACID TO FORM THE CORRESPONDING 16,17-EPOXIDE, REDUCING THE 3-KETO GROUP AND THE EPOXIDE WITH LITHIUM ALUMINUM HYDRIDE TO FORM A MIXTURE OF $4-ANDROSTEN-3A,17A-DIOL AND $4-ANDROSTEN3B,17A-DIOL AND SELECTIVELY OXIDIZING THE 3-HYDROXY GROUP OF THE MIXTURE WITH MANGANESE DIOXIDE
 7. $5,16-ANDROSTADIEN-3B-OL. 